tbuckley/cabot-search huggingface dataset:
Clinical validation of an activity-based enzyme assay for early stage lung cancer.
Authors: Paul W. Dempsey, Cristina-Mihaela Sandu Aparicio, Ricardo Gonzalezirias, Spencer Hantula, Mari Kagawa, Stefan H. Bossmann, Obdulia Covarrubias-Zambrano, Alykhan S. Nagji, Nirmal K Veeramachaneni, Nezih O. Ermerak, Derya Kocakaya, Tunc Lacin, Bedrettin Yildizeli, Sara Witting Christensen Wen, Line Nederby, Torben Hansen, Ole Hilberg
Journal: Journal of Clinical Oncology (2023)

8533 Background: The USPSTF guidelines recommend annual LDCT scans for 15.5 million adults with a heavy smoking history. While LDCT can reduce deaths by 20%, screening compliance remains low. A blood test with clinically useful, cost effective performance could improve compliance and access when integrated with the standard of care. We describe here a lyophilized nanosensor system for detecting protease enzyme activity in sera with clinically useful diagnostic activity in early stage lung cancer. We evaluated the performance of the assay by examination of prospectively collected sera for detection of cancer in high risk patients. Methods: Sera were obtained in multiple independent studies to include pathologically confirmed, treatment naive lung cancer patients and LDCT confirmed negative individuals. Protease activity was measured on 18 different nanosensors built with protease targets mainly selective for members of the Matrix Metalloproteinase and Cathepsin families. Lyophilized plates were incubated with serum and enzyme activity was measured indirectly as a continuous variable by a fluorescent plate reader. A machine learning modeling tool (Emerge) was used to detect signal associated with a cancer “fingerprint” of protease activity. The analysis stratified allocation into training and testing sets of 250 samples each and reserved a third out of sample validation set (250 samples) for reporting. Results: 750 clinical samples included 30% lung cancers, 63% males, 91% smokers, and an average age of 63 years (SD=9). Cancer cases were distributed across stages I (41%), II (17%), III (20%) and IV (20%) with 5% unknown. Histological classification included 59% adenocarcinoma, 31% squamous cell and 11% other subtypes. Using an Emerge model with only nanosensor activity and gender as inputs, we evolved a balanced algorithm. The algorithm can be further modified to favor sensitivity or specificity depending on the application by applying model weighting factors. We report the performance observed in the 250 out of sample validation set at three points on this spectrum (Table). Among Stage I cancer samples, the balanced algorithm had an accuracy of 90% (26/29). Conclusions: Current LDCT tools show low compliance. We demonstrate clinical validity of a cost effective tool to detect lung cancer in support of LDCT screening. Based on a simple blood sample, the current test may predict early stage lung cancer with an accuracy of 90%. The performance suggests applications in LDCT compliance, post LDCT management, and eventually screening. A clinically validated version of this technology is being evaluated as a triage tool for LDCT screening. [Table: see text]
Melanomas lacking HLA class I expression and response to checkpoint inhibitor.
Authors: Paul B. Chapman, Vetri Sudar Jayaprakasam, Margaret K. Callahan, Alexander Noor Shoushtari, Michael A. Postow, Cecilia Lezcano, Jedd D. Wolchok, Subhiksha Nandakumar, Walid Khaled Chatila
Journal: Journal of Clinical Oncology (2023)

9553 Background: The current paradigm of how checkpoint inhibitors (CPIs) mediate anti-tumor effects relies on αβ T cells as the effector cells. However, HLA class I allele expression loss is common in melanoma, and in some cases, both β2-microglobulin (β2m) alleles are silenced, which results in complete loss of HLA I expression. We reasoned that if CPI therapy requires αβ T cells as the effector cells, melanoma tumors with biallelic loss of β2m could not present antigen to αβ T cells and should never respond to CPI. Methods: We screened the 2754 melanoma patients (pts) whose tumors had been genotypically analyzed using MSK-IMPACT, a hybridization capture-based next-generation assay for targeted deep sequencing of all exons and selected introns of up to 505 genes, including β2m. We identified 13 pts who had been treated with CPI, were evaluable for response and progression-free survival, and whose pre-treatment melanoma was found to have biallelic loss of β2m. In 1 pt, only a post-treatment tumor was available for genetic testing for β2m loss but lack of β2m expression in a pre-treatment tumor was confirmed by immunohistochemistry (IHC). Pts were assessed for clinical responses using RECIST 1.1. We recorded best overall response, duration of response, and overall survival. When available, pre-treatment tumor tissue was assessed by IHC for β2m and HLA class I expression, and for lymphocytic infiltrates expressing CD3, CD4, CD8, and CD56. Results: Anti-tumor responses were observed in 3/13 patients (23%); 2 PRs, 1 metabolic CR lasting for 24, 9.4, and 6.4 months, respectively. Responses were to ipilimumab (ipi) (N=2) and ipi/nivolumab (N=1). One pt responding to ipi had progressed on pembrolizumab; the other 2 responders were treatment-naïve. One pt died 11.5 months after starting treatment; the other 2 pts remain alive 5.5 and 8.9 years after starting treatment. IHC confirmed the lack of cell surface expression of β2m and HLA class I in all 5 tumors available for IHC staining. IHC evaluations of lymphocyte infiltrates in tumors from 1 responder and 4 non-responders showed variable degrees of CD3 + tumor infiltrating lymphocytes (TIL) with CD4 + T cell predominance. Interestingly, the 1 responder had the least dense pretreatment TIL among the 5 cases. In all 5 tumors, CD56 + lymphocytes, indicating NK cells, were rare-to-absent. Conclusions: Melanomas lacking HLA class I expression can respond to CPI therapy. Although all patients ultimately progressed, some responses were long-lived and 2 of 3 patients remain alive &gt;5yrs. It seems unlikely that traditional CD8 + T cells are mediating these responses but more work needs to be done to identify the effector cells in these cases.
A systematic comparison of whole genome sequencing and targeted panel sequencing for precision oncology.
Authors: Ji-Hyung Park, Erin Connolly-Strong, Young Tae Kim, Young Seok Ju
Journal: Journal of Clinical Oncology (2023)

8546 Background: The analysis of the cancer genome provides clinically meaningful information such as actionable cancer driver mutations. Whole genome sequencing (WGS) provides a complete mutational landscape at an affordable cost thereby having increase clinical utility compared to the usual approach of targeted panel sequencing (TPS). To understand the capabilities of WGS in oncology, we conducted a study in lung adenocarcinomas. Methods: We produced WGS (surgically resected tumor tissues and matched blood; mean coverage 42x) and TPS (tumor only; SNUH panel encompassing 75 cancer genes; mean coverage 904x) through the Illumina sequencing platform and conducted comprehensive bioinformatic analyses. Oncogenic driver events, including single base substitution (SBS), insertion or deletion (INDEL), complex deletion-insertion, and fusion oncogene, were investigated in both datasets. Lastly, we compared the pattern-based mutational features, such as tumor mutational burden (TMB), mutational signatures, and copy number changes which is associated with genomic instability. Results: In 60 lung adenocarcinomas, the TPS method identified 120 driver mutations from the 75 targeted genes. Of these, 114 mutations were also detected by the WGS method, showing 95.0% sensitivity of WGS in detection of core driver mutations. In uncovered genomic regions by TPS, WGS captured 9 additional driver mutations (such as loss-of-function mutations in PIK3R2, ARID2, and APC) and 37 copy number variations (such as amplification of LMO and SMO, deletion of PIK3R1 and APC) in the cancer genes. TMB calculation is straightforward in WGS however, sophisticated considerations were necessary in TPS for TMB, to remove false positives and germline mutations. TPS showed a good capability for identifying hypermutator tumor samples, but a quantitative estimation was not always feasible due to the substantial background fluctuation, particularly for INDELs. Mutational signatures are unique combinations of mutation types in a given sample, which can give important clues to the mechanism underlying mutations. TPS showed adequate mutational signatures (cosine similarity &gt; 0.7), but was not constantly satisfactory in tumors with high TMB ( &gt; 20,000 genome wide SBS and INDELs). In TPS, approximately 30% of high TMB tumors represented marginal cosine similarity (0.5-0.7), and tobacco smoking related signature (SBS 4) found in WGS was captured only in 50% of the associated cases (9 out of 18). For DNA copy number changes and loss-of-heterozygosity analyses, WGS showed a much higher resolution. Conclusions: Our study demonstrates that WGS has comparable capabilities for the detection of driver mutations in core oncogenes and tumor suppressor genes. WGS was superior for pattern-based features, such as TMB, mutational signatures, and copy number changes. WGS is a medically necessary more comprehensive approach to precision oncology.
Racial and ethnic disparities in quality of diagnostic evaluation for uterine cancer among Medicare patients.
Authors: Xiao Xu, Ling Chen, Jason Dennis Wright
Journal: Journal of Clinical Oncology (2023)

5600 Background: Uterine cancer is the most common gynecologic malignancy. As there is no routine screening for uterine cancer, appropriate evaluation of presenting symptoms is crucial for early diagnosis. We examined racial/ethnic disparities in the quality of diagnostic evaluation received by Medicare patients with uterine cancer. Methods: Using the Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified patients ≥65 years with uterine cancer diagnosed in 2008-2017 who presented with abnormal uterine bleeding (AUB, the most common symptom of uterine cancer). Patients with other cancer or unknown race/ethnicity were excluded. Race/ethnicity was categorized as White, Black, Hispanic, or Other (including American Indian/Alaska Native and Asian/Pacific Islander). Quality of diagnostic evaluation was measured by: 1) not receiving guideline-recommended diagnostic procedures (yes/no), and 2) number of days between AUB presentation and first diagnostic procedure. We compared these measures across racial/ethnic groups using multivariable regressions adjusting for patient sociodemographic characteristics, comorbid conditions, histology, and tumor grade. We further examined racial/ethnic differences in stage at diagnosis before vs. after accounting for these quality indicators. Results: The sample included 23,017 patients. Compared to White patients, Black, Hispanic, and Other patients were younger; more likely to reside in a metropolitan area, lack preventive care in the past year, or have comorbidities; and tended to have uterine cancer of non-endometrioid types and higher grade (p&lt;0.001 for all). A larger proportion of Black than White patients did not receive guideline-recommended diagnostic procedures (Black: 9.6% vs. White: 5.0%, p&lt;0.001; adjusted odds ratio [aOR] = 1.45, 95% CI: 1.20-1.74). Time from AUB presentation to first diagnostic procedure was longer for Black than White patients (90 th percentile: 34 vs. 21 days, p&lt;0.001; adjusted mean ratio = 1.38, 95% CI: 1.21-1.57). Black patients were more likely than White patients to be diagnosed at regional (aOR = 1.18, 95% CI: 1.04-1.33) or distant stage (aOR = 1.27, 95% CI: 1.06-1.52), rather than localized stage, even after adjusting for other characteristics. Further adjusting for quality of diagnostic evaluation slightly reduced Black-White differences in stage at diagnosis (regional: aOR = 1.16, 95% CI: 1.03-1.32; distant: aOR = 1.23, 95% CI: 1.03-1.48). Hispanic and Other patients also experienced delay in time to first diagnostic procedure, but they did not differ from White patients in receipt of guideline-recommended diagnostic procedures or stage at diagnosis. Conclusions: There were racial/ethnic disparities in the quality of diagnostic evaluation received by Medicare patients with uterine cancer, which may partially explain Black-White differences in their stage at diagnosis.
Subsequent meningiomas in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Tab Cooney, Yan Chen, Yan Yuan, Robert Thomas Galvin, Wendy M. Leisenring, Susan A. Smith, Rebecca M. Howell, Michael A. Arnold, Miriam Conces, Daniel C. Bowers, Yutaka Yasui, Lisa Diller, Gregory T. Armstrong, Joseph Philip Neglia, Lucie Marie Turcotte
Journal: Journal of Clinical Oncology (2023)

10058 Background: Meningiomas are the most common subsequent central nervous system tumor among aging survivors of childhood cancer, yet incidence across the lifespan, occurrence of multiple meningiomas, and risk for mortality are not established. Methods: Meningiomas were identified by self-report and validated with pathology/medical records. Twenty-year cumulative incidence of meningioma (95% confidence interval) was estimated and multivariable models assessed demographic- and treatment-related meningioma risk factors. Results: Among 24,902 5-year survivors of childhood cancer diagnosed 1970-1999, we identified 472 survivors with 710 meningiomas, 145 (20.4%) of which were WHO grade 2/3. Among survivors with meningioma, 137 (28%) had ≥2 meningiomas, and 80 (16%) met criteria for meningiomatosis. The median latency from childhood cancer to first meningioma diagnosis was 26.2 years (range 5.6-48.2), and the median time from first to second meningioma (among those without meningiomatosis) was 1.4 years (range 0-30.2 years). The twenty-year cumulative incidence did not significantly decrease between survivors diagnosed in the 1970s (0.58, 95% CI 0.41-0.79) and the 1990s (0.42, 95% CI 0.32-0.55). In multivariable analysis, female sex (HR 1.52, 95% CI 1.21-1.91) and all cranial radiotherapy dose levels ( &gt; 0-30Gy, HR 57.0, 95% CI 7.93-419.60; 30.1-50 Gy, HR 228.90, 95% CI 30.89-1695.99; &gt; 50 Gy, HR 113.29, 95% CI 15.09-850.34) were associated with increased meningioma risk, while older age at diagnosis (10-14 years, HR 0.60, 95% CI 0.44-0.82; 15-20 years, HR 0.35, 95% CI 0.22-0.55) was associated with reduced meningioma risk. Among 71 deaths in survivors with meningioma, the most prevalent cause of death was meningioma (N = 25, 35.2%). The 5-year all-cause mortality from first meningioma diagnosis was 4.20% (95% CI: 2.44-5.96%). Conclusions: In conclusion, cranial radiation, younger diagnostic age and female sex were identified as independent meningioma risk factors in, to our knowledge, the largest study to date. The risk for meningioma-associated mortality argues for assertive meningioma surveillance and treatment in this population.
Outcomes among children with hearing loss admitted with acute lymphocytic leukemia.
Authors: Kamleshun Ramphul, Shivani Sharma, Suma Sri Chennapragada, Mehndi Dandwani, Renuka Verma, Alekhya Pagidipally, Shaheen Sombans, Sailaja Sanikommu, Yogeshwaree Ramphul, Balkiranjit Kaur Dhillon, Petras Lohana, Vijay Kumar, Fnu Arti
Journal: Journal of Clinical Oncology (2023)

e22000 Background: Hearing loss among children can influence their growth and development. It can also influence how they seek help for any significant health-related complications. While some studies have highlighted such issues in the adult population, there needs to be more data on pediatric hospitalizations. We, therefore, attempted to conduct a retrospective analysis among Acute lymphocytic leukemia (ALL) cases in children with a diagnosis of hearing loss. Methods: Children below 18 were recruited from the 2016-2020 National Inpatient Sample (NIS) provided by the Healthcare Cost and Utilization Project. The diagnoses of ALL and hearing loss (of any form) were found using the International Classification of Disease 10th Revision (ICD-10) codes. We evaluated the presence of hearing loss in various patient groups and compared different potential complications of ALL between children with hearing loss (vs. those without). Results: We found 123430 weighted cases of ALL among children of ages 0-17 (inclusive) in the United States. Nine hundred fifty-five children (0.8%) also reported a diagnosis of hearing loss. Such diagnosis was more likely in patients who were Hispanics (vs. White, aOR1.458, 95% CI 1.247-1.703, p &lt; 0.01) or of ages 11-17( vs. ages 0-10, aOR 1.920, 95% CI 1.679-2.196, p &lt; 0.01). Meanwhile, children with ALL and hearing loss are less likely to be covered by Private Insurance (vs. Medicaid, aOR 0.811, 95% CI 0.699-0.941, p &lt; 0.01), and less likely to be females (aOR 0.469, 95% CI 0.402-0.547, p &lt; 0.01). Moreover, the presence of a diagnosis of hearing loss among ALL patients was also associated with a higher odd of septicemia (aOR 2.211, 95% CI 1.797-2.721, p &lt; 0.01), use of palliative care (aOR 3.111, 95% CI 2.252-4.299, p &lt; 0.01), and mortality (aOR 2.604, 95% CI 1.659-4.087, p &lt; 0.01). Conclusions: Our analysis provides a novel perspective on the characteristics of hearing loss patients with ALL. Racial and socio-economic differences were confirmed. Furthermore, as they have higher odds of being under palliative care, they may also be sicker, which explains the higher odds of complications such as septicemia and mortality during hospitalization. Further studies must be done to understand the disparities seen in our study in a more clinical setting and address them appropriately.
Affecting burden and cost of care for the caregiver of dependent patients with advanced stage of cancer who had an arrangement for expected death at home.
Authors: Kanokrat Palanupap
Journal: Journal of Clinical Oncology (2023)

e24000 Background: The terminal stage cancer patients suffer from disease and related therapeutic processes, lead to increasing need for caring from their caregivers. This affects the quality of life(QOL) of caregivers. Currently, there is no data on burden of caregivers who caring for cancer patients who are choose to die at their home. Objective: This study examined burden of caregivers, impact on QOL and satisfaction of caregivers for patients with terminal cancer, comparing in the group of patients who die at home versus at hospital, comparing in regular care group(RC) versus palliative care group(PC). Methods: The semi-qualitative-quantitative study enrolled caregivers of advance cancer patients who had PPS &lt; 60 at Ramathibodi Hospital from Dec 2021-Nov 2022. We assessed participants on 3-time-points (enrolment, 1, 2 months) for QOL and burden via telephone interviews, questionnaires by EQ5D5L and Zarit Burden. If the patients passed away, we interviewed caregivers in qualitative study. Analysis responses were recorded, transcribed and organized thematically analyzed. Analysis stratified on care with palliative care or not, and place of death. Results: We enrolled 108 participants, child (56%) and spouses (29%). They spent carring time average of 16.56 hr/day. 52 patients have passed away: home death(34) and hospital death(18). No significant difference in burden score and QOL between RC and PC. Burden score significantly increasing when time of death approach in both groups. However, significantly higher satisfaction score in caregivers of patients who died at home(P &lt; 0.001). In patient who died in hospital, early integrated palliative showed significantly higher satisfaction score(P = 0.046). Qualitative analysis revealed 3 primary themes, 1) caregiver burden is increasing and chronic stress condition until the death of their loves and still continue post their death 2) need more help in coping and nursing strategies, more early palliative care can relieve their distresses 3) opinion of the caregivers in group of hospital death, If they could turn back time, they would have promised to look after their lovers better in changing the pass away at their home. Conclusions: Caregivers for terminal cancer patients have a high burden. However, caregiver of patients who died at their home rather have more satisfaction. Early integrated palliative care improves satisfaction in caregiver of patients who died at hospital. [Table: see text]
Investigation of the prognostic significance of CD5, CD117, EZH2, POU2F3, MTAP and BAP1 in thymic carcinoma.
Authors: Julia R. Naso, Sarah M. Jenkins, Julie A. Vrana, Justin W. Koepplin, Kenneth R. Olivier, Stephen D. Cassivi, Julian R. Molina, Anja C. Roden
Journal: Journal of Clinical Oncology (2023)

e20646 Background: Thymic carcinomas tend to be aggressive malignancies with variable patterns of immunostaining. We aimed to assess whether the outcome of patients with thymic carcinomas was associated with immunoreactivity for conventional and emerging immunohistochemical markers of thymic carcinoma versus thymoma. Methods: Scoring of CD5, CD117, EZH2, POU2F3, BAP1, and MTAP immunohistochemistry on whole slide sections was compared to overall survival (OS) and progression free survival (PFS) for 36 thymic carcinoma patients, 28 of whom had complete tumor resection and 8 of whom had incomplete tumor resection. Results: Positive CD5 staining (defined as staining in ≥50% of tumor cells) was present in 13/36 cases (36%) and was significantly associated with longer OS (P = 0.005, hazard ratio = 0.18, CI 0.03-0.63) but not PFS (P = 0.14, hazard ratio = 0.48, CI 0.16-1.26), whereas the other markers were not significantly associated with OS or PFS. Positive CD5 staining remained significantly associated with OS in squamous cell carcinoma subgroup analysis (n = 23, HR = 0.17, CI 0.03-0.65, P = 0.009), patients who did not receive neo-adjuvant treatment (n = 24, HR = 0.21, CI 0.03-0.85, P = 0.03) and after adjusting for incomplete resection (HR = 0.20, CI0.03-0.73, P = 0.01), M1 stage (HR = 0.19, CI 0.03-0.71, P = 0.01) or neoadjuvant treatment (HR = 0.19, CI 0.03-0.71, P = 0.01) in bivariate models. Positive CD5 staining was also significantly associated with age ≥60 years, absence of neoadjuvant treatment, and positive POU2F3 staining. Conclusions: CD5 staining in ≥50% of tumor cells was significantly associated with longer OS for thymic carcinoma patients. Our study supports the notion that CD5 immunohistochemistry may have utility as a prognostic marker for thymic carcinomas.